Topical KINOSTAT™ ameliorates the clinical development and progression of cataracts in dogs with diabetes mellitus

Abstract

Objective To determine whether topical administration of the aldose reductase inhibitor KinostatÔ can ameliorate the onset or progression of cataracts in dogs with naturally occurring diabetes mellitus (DM). Materials and Methods A randomized, prospective, double-masked placebo control pilot study was conducted with 40 dogs newly diagnosed with DM with no or minimal lens changes. Twenty-eight dogs received KinostatÔ and 12 dogs received placebo. Procedures Owners administered the agent into both eyes three times daily for 1 year and compliance was monitored with log sheets. Complete ophthalmic examinations were performed on dilated eyes at the time of enrollment and 1, 2, 3, 6, and 12 months into treatment. Cataract severity was assessed on a scale of 0-3. At 12 months, full bloodwork, including HbA1C and blood Kinostat TM levels were performed.Results After 12 months of treatment, the cataract score in the placebo group significantly increased with seven dogs (14 eyes) developing mature cataracts, two dogs (4 eyes) developing cortical opacities, and one dog (2 eyes) developing equatorial vacuoles with mild punctate cortical opacities. In contrast, the cataract score in the Kinostat TM treated dogs was significantly less with seven developing anterior equatorial vacuoles, two developing incipient anterior cortical cataracts, and four developing mature cataracts. In fact, the cataract scores of the Kinostat TM group at 12 months did not significantly increase from the score at the time of enrollment. The HbA1C values between the two groups after 12 months of treatment were similar, and no blood levels of Kinostat TM were found in any enrolled dog.Conclusion The onset and/or progression of cataracts in dogs with DM can be significantly delayed by topical administration of KinostatÔ.

Molecular Interactions and Implications of Aldose Reductase Inhibition by PGA1 and Clinically Used Prostaglandins

“…In addition, strategies using inhibitors have provided numerous pieces of evidence to implicate AKR1B1 in diabetic cataract in various experimental models. Thus, topical administration of an aldose reductase inhibitor delays the development of cataracts in diabetic dogs (Kador et al, 2010), and oral treatment with another inhibitor prevents their progression in rats (Kawakubo et al, 2012). The results presented herein show that both PGA 1 and PGE 1 reduce the formation of sorbitol in isolated rat lenses exposed to high glucose, thus opening the way for in vivo studies.…”

Osmotic stress, not aldose reductase activity, directly induces growth factors and MAPK signaling changes during sugar cataract formation

“…Kinoshita was the first to demonstrate the hyperosmotic effects of intracellular sorbitol or galactitol accumulation and to postulate that the resulting cellular swelling can lead to increased membrane permeability and a series of complex biochemical changes associated with sugar cataract formation (Kador and Kinoshita, 1984; Kinoshita, 1974; Kinoshita et al, 1979). The central role of AR in sugar cataract formation has been confirmed by the ability of ARIs to prevent sugar cataract formation in diabetic or galactosemic animals (Kador and Kinoshita, 1984; Kador et al, 2010b; Kinoshita, 1974; Mizuno et al, 1990). …”

Mutations and mechanisms in congenital and age-related cataracts

“…These anti-aggregation or chaperone approaches might be combined with inhibitors of the UPR to help mitigate the effects of any unstable protein resistant to small molecule chaperones. In addition, it has been demonstrated that topical administration of an aldose reductase inhibitor (Kinostat) delays onset and progression of cataracts in dogs with naturally occurring diabetes mellitus (Kador et al, 2010). While these preliminary results with small molecules are promising, it is noteworthy that several other animal-model studies of small molecules with anti-oxidant and/or anti-aggregation (chaperone) properties including; plant-flavonoids, aspirin, N-acetyl carnosine, curcumin, caffeine, and multivitamins have not resulted in universal clinical approval for use as anti-cataract drugs in humans.…”